Molecule Hijacks Enzyme To Boost Alcohol Metabolism

An experimental compound empowers an enzyme to help process acetaldehyde, a toxic metabolite of alcohol, according to new research supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The findings, now online in the Proceedings of the National Academy of Sciences (PNAS), might lead to new treatments to help people with impaired ability to metabolize acetaldehyde and other toxic substances. NIAAA is part of the National Institutes of Health.

"This intriguing finding could have important implications," said NIAAA Director George F. Koob, Ph.D. "Developing pharmacologic agents that alter an enzyme’s substrate specificity is a unique approach that may have wide clinical application in treating patients with impaired ability to detoxify toxic substances. We look forward to further research aimed at translating these laboratory discoveries into possible treatments for people."

After alcohol is consumed, it is first metabolized into acetaldehyde, a toxic chemical that can cause DNA damage and cancer. In the liver, aldehyde dehydrogenase 2 (ALDH2) is the main enzyme responsible for breaking down acetaldehyde into acetate, a nontoxic metabolite. It also removes other toxic aldehydes that can accumulate in the body. An estimated 560 million people in East Asia, and many people of East Asian descent, carry a genetic mutation that produces an inactive form of ALDH2. When individuals with the ALDH2 mutation drink alcohol, acetaldehyde accumulates in the body, resulting in facial flushing, nausea, and rapid heartbeat. People with the ALDH2 mutation are also at increased risk for cancers of the mouth, esophagus, and other areas of the upper aerodigestive tract.

Researchers led by Daria Mochly-Rosen, Ph.D., a professor in the Department of Chemical and Systems Biology at Stanford University, Stanford, California, have developed a number of small molecules called aldehyde dehydrogenase activators, or Aldas, that in previous studies have been found to increase the activity of the ALDH2 enzyme.

In the current study, they tested a new compound, Alda-89, which they found could provide another aldehyde dehydrogenase enzyme – ALDH3A1 -- with accelerated acetaldehyde-metabolizing powers that it ordinarily does not possess.

“We targeted the ALDH3A1 enzyme because it metabolizes acetaldehyde poorly and is highly expressed in the upper airway, stomach and gut, all tissues that are prone to cancer development in people who drink alcohol in excess,” said Dr. Mochly-Rosen. “By recruiting ALDH3A1 to metabolize acetaldehyde we could perhaps accelerate the elimination of acetaldehyde from tissues that are more vulnerable to its carcinogenic effects.”

Dr. Mochly-Rosen and her colleagues showed that Alda-89 increased acetaldehyde metabolism both in normal mice and in mice carrying the ALDH2 mutation found in the East Asian population. The researchers also showed that, in test tube analyses, acetaldehyde removal was faster when they combined Alda-89 with Alda-1, a compound previously shown to activate ALDH2, compared with activating each ALDH alone. They also showed in animal studies that mice treated with the combination of Alda-89 and Alda-1 exhibit accelerated recovery from alcohol intoxication.